Lymphotoxin α fine-tunes T cell clonal deletion by regulating thymic entry of antigen-presenting cells
| Autor: | Magali Irla, Oriane Cédile, Noëlla Lopes, Arnauld Sergé, Jonathan Charaix |
|---|---|
| Přispěvatelé: | Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Neurobiology Research [Odense, Denmark] (Institute of Molecular Medicine), University of Southern Denmark (SDU), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), This work was supported by institutional grants from Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique and Aix-Marseille Université, the Swiss National Science Foundation (PZ00P3-131945 to M.I.), the Marie Curie Actions (Career Integration Grants, CIG_SIGnEPI4Tol_618541 to M.I.), the Jules Thorn Foundation (to M.I.), Novonordisk Foundation (6131 to O.C.) and Augustinus Foundation (14-2913 to O.C.). We acknowledge financial support from n°ANR-10-INBS-04-01 France Bio Imaging. N.L. and J.C. are supported by a PhD fellowship from Aix-Marseille University and the Ministère de l’Enseignement Supérieur et de la Recherche, respectively., Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), IRLA, Magali, Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male T-Lymphocytes General Physics and Astronomy Macrophages/immunology Ligands Lymphotoxin-alpha/metabolism Immune tolerance Chemokine receptor Mice 0302 clinical medicine lcsh:Science Lymphotoxin-alpha Antigens/immunology Multidisciplinary Thymocytes Microscopy Confocal Chemokines/immunology NF-kappa B Receptors CCR2/metabolism hemic and immune systems 3. Good health Cell biology Thymocyte medicine.anatomical_structure [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology [SDV.IMM]Life Sciences [q-bio]/Immunology Female Chemokines Lymphotoxin alpha Thymus Gland/immunology Receptors CCR2 T cell Science Antigen-Presenting Cells Clonal Deletion Bone Marrow Cells Mice Transgenic Thymus Gland Biology General Biochemistry Genetics and Molecular Biology Clonal deletion Article 03 medical and health sciences medicine Antigen-Presenting Cells/immunology Immune Tolerance Animals Antigens Antigen-presenting cell Macrophages General Chemistry Dendritic Cells T-Lymphocytes/immunology Coculture Techniques 030104 developmental biology Dendritic Cells/immunology NF-kappa B/metabolism Thymocytes/immunology lcsh:Q Bone Marrow Cells/immunology Gene Deletion 030215 immunology Homing (hematopoietic) |
| Zdroj: | Nature Communications Nature Communications, Nature Publishing Group, 2018, 9 (1), pp.1262. ⟨10.1038/s41467-018-03619-9⟩ Nature Communications, Vol 9, Iss 1, Pp 1-16 (2018) Nature Communications, Nature Publishing Group, 2018, 9, ⟨10.1038/s41467-018-03619-9⟩ Lopes, N, Charaix, J, Cédile, O, Sergé, A & Irla, M 2018, ' Lymphotoxin α fine-tunes T cell clonal deletion by regulating thymic entry of antigen-presenting cells ', Nature Communications, vol. 9, 1262 . https://doi.org/10.1038/s41467-018-03619-9 Nature Communications, 2018, 9 (1), pp.1262. ⟨10.1038/s41467-018-03619-9⟩ Nature Communications, 2018, 9, ⟨10.1038/s41467-018-03619-9⟩ |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-018-03619-9⟩ |
| Popis: | Medullary thymic epithelial cells (mTEC) purge the T cell repertoire of autoreactive thymocytes. Although dendritic cells (DC) reinforce this process by transporting innocuous peripheral self-antigens, the mechanisms that control their thymic entry remain unclear. Here we show that mTEC-CD4+ thymocyte crosstalk regulates the thymus homing of SHPS-1+ conventional DCs (cDC), plasmacytoid DCs (pDC) and macrophages. This homing process is controlled by lymphotoxin α (LTα), which negatively regulates CCL2, CCL8 and CCL12 chemokines in mTECs. Consequently, Ltα-deficient mice have increased expression of these chemokines that correlates with augmented classical NF-κB subunits and increased thymic recruitment of cDCs, pDCs and macrophages. This enhanced migration depends mainly on the chemokine receptor CCR2, and increases thymic clonal deletion. Altogether, this study identifies a fine-tuning mechanism of T cell repertoire selection and paves the way for therapeutic interventions to treat autoimmune disorders. Autoreactive T cells are removed during their development in the thymus through the functions of medullary thymic epithelial cells (mTEC) and dendritic cells (DC), a process termed negative selection. Here the authors show that mTEC-T cell crosstalk and lymphotoxin α signalling are essential for the proper recruitment of DCs into the thymus. |
| Databáze: | OpenAIRE |
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